The Chlamydiae are obligate intracellular pathogens that cause a range of acute and chronic diseases including trachoma, conjunctivitis, pelvic inflammatory disease and atypical pneumonias. In infected cells, Chlamydia efficiently acquires host-derived membrane lipids despite an apparent isolation of the bacterial - containing vacuole (""""""""inclusion"""""""") from classical endocytic and secretory membrane traffic. Because Chlamydiae are not amenable to genetic manipulation, little is known about the molecular basis for bacteria- mediated acquisition of eukaryotic lipids. We have determined that Chlamydia trachomatis synthesizes proteins that target eukaryotic lipid droplets (LD) -a lipid storage organelle. We have characterized the interaction between C. trachomatis and IDs and found that chlamydial infection led to the proliferation of a subclass of IDs on the surface of the inclusion. Furthermore, pharmacological disruption of LD biogenesis inhibited chlamydial replication. We hypothesize that Chlamydia co-opts the function of IDs to establish a growth permissive environment within infected cells. We propose to: 1) characterize the impact of chlamydial infection on LD functions by cell biological and proteomic approaches and to determine the role of individual LDs proteins in Chlamydia pathogenesis by RNA interference-mediated disruption of key LDs components, 2) identify the cellular targets of Chlamydia LD-tropic proteins through state-of-the art yeast genomics tools and affinity-based isolation of binding partners from mammalian expression cell lines. This is the first example of a bacterial pathogen targeting LDs, providing a unique opportunity to investigate a novel mechanism of pathogen-mediated eukaryotic organelle subversion. Our proposed approaches will define the cellular pathways affected by Chlamydia LD-tropic proteins, identity novel targets for therapeutic intervention and establish the role of these poorly characterized organelles in Chlamydia infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Special Emphasis Panel (ZRG1-HIBP-H (01))
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Hiltke, Thomas J
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Duke University
Schools of Medicine
United States
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Saka, Hector Alex; Thompson, J Will; Chen, Yi-Shan et al. (2015) Chlamydia trachomatis Infection Leads to Defined Alterations to the Lipid Droplet Proteome in Epithelial Cells. PLoS One 10:e0124630
Saka, Hector Alex; Valdivia, Raphael (2012) Emerging roles for lipid droplets in immunity and host-pathogen interactions. Annu Rev Cell Dev Biol 28:411-37
Jorgensen, Ine; Bednar, Maria M; Amin, Vishar et al. (2011) The Chlamydia protease CPAF regulates host and bacterial proteins to maintain pathogen vacuole integrity and promote virulence. Cell Host Microbe 10:21-32
Saka, Hector A; Thompson, J Will; Chen, Yi-Shan et al. (2011) Quantitative proteomics reveals metabolic and pathogenic properties of Chlamydia trachomatis developmental forms. Mol Microbiol 82:1185-203
Vignola, Mark J; Kashatus, David F; Taylor, Gregory A et al. (2010) cPLA2 regulates the expression of type I interferons and intracellular immunity to Chlamydia trachomatis. J Biol Chem 285:21625-35
Saka, Hector Alex; Valdivia, Raphael H (2010) Acquisition of nutrients by Chlamydiae: unique challenges of living in an intracellular compartment. Curr Opin Microbiol 13:4-10
Cocchiaro, Jordan L; Valdivia, Raphael H (2009) New insights into Chlamydia intracellular survival mechanisms. Cell Microbiol 11:1571-8
Kumar, Yadunanda; Valdivia, Raphael H (2009) Leading a sheltered life: intracellular pathogens and maintenance of vacuolar compartments. Cell Host Microbe 5:593-601
Valdivia, Raphael H (2008) Chlamydia effector proteins and new insights into chlamydial cellular microbiology. Curr Opin Microbiol 11:53-9
Kumar, Yadunanda; Valdivia, Raphael H (2008) Actin and intermediate filaments stabilize the Chlamydia trachomatis vacuole by forming dynamic structural scaffolds. Cell Host Microbe 4:159-69

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